Process of preparing 2, 2-diphenyl-3-methyl-4-dimethylamino-butyronitrile



Patented Aug. 19, 1952 PROCESS 'OF PREPARING 2,2-DIPHENYL-3-TMETHYL-4-DIMETHYLAM'INO-BUTYRONI- 'rnILE .Earl .M. Chamberlin, Rahway,and Max Tishler;

Westfield, N. J., assignors to Merck & 00., Inc,

V Rahway, N. J a corporation of New Jersey No Drawing. Application April9, 1949, Serial No. 86,596

6 Claims. (01. 260-465) This invention relates to. the manufacture ofcompounds possessing analgesic and anesthetic action. Inparticular, itisconcerned with an improved syntheticmethod for preparing '2,2-diphenyl3-methyl-4-dimethylamino butyronitrile and withnovel chemical compoundsuseful as intermediates in the preparation of this compound.2,2-diphenyl-3emethyl 4-dimethylamino-butyronitr-ile is itself .animportant intermediate in the synthesis of isoamidone,l-dimeth-ylamino-2-methyl-3,3-diphenylhexanone 4 and salts thereof.Isoamidoneand its salts possess analgesic action and maybe used assubstitutes formorphine.

2,2 diphenyl 3 methyl J- 4 dimethylaminobutyronitrile has been prepare'dpreviously by reacting 1-dimethylamino-2-chloropropane withdiphenylacetonitrile as described by Schultz et al. (J. A. C. S. 69,188-189, Jan. 1947). As pointed out by these workers, however, when2,2-diphenyl 3 methyl 4 dimethlamino-butyronitrile is prepared by thisprocedure, there is obtained, at the same time and mixed with thiscompound, the isomeric nitrile, 2,2-diphenyl-4- methyl-4dimethylaminoebutyronitrile. The latter nitrile isomer constitutes anunwanted byproduct since it cannot be converted to isoamidone.

Moreover, the preparation of isoamidone direct- 1y from the mixture ofisomeric nitriles has not proven feasible; "In order to prepareisoamidone it has therefore previously been necessary to isolate thedesired 2,2-diphenyl 3-methyl 4 dimethyl ainino-butyronitrile from themixture and this has necessitated a complicated separation procedurewhich results in a considerable loss of the desired isomer. 1

'-It'-is now discovered that the desired 2,2-diphenyl- 3 methyl 4dimethylamino-butyronitrile can be prepared by a novel process whichdoes not produce any of the unwanted isomeric nitrile. This improvedmethod thus eliminates the loss due to formation .of the icy-productisomer and at the same time avoids the need for a complicatedseparationprocedure with its attendant'losses of the desired isomer.

*This novel process is conducted asfol'lows: Propylene chlorohydrin(compound 1 below) is reacted with an organic sulfonyl chloride(compound 2) to produce the corresponding 1- methyl -'2 chloroethylsulfonate compound 3). This compound is then treated with the reactionproduct of diphenyl acetonitrile and sodamide to produce 2,2diphenyl-3-methyl-4-chlorobutyronitrile (compound 4.) which is reactedwith dimethylamine to .'form 2,2-diphenyl-3-methyl-4-dimethylaminobutyronitrile .(compound 5). These reactions may bechemically represented as follows:

'omononon.c1+ RSOzCl CHconcHici l(CaHs)2CH@/N N N z HahNH(CeH5)2C-CHCH2N(OH3)2 (C HQAC-GHQHJCI THa JHa 0N ON Under theseconditions, the reaction is usually complete after a reaction period of1 to 3 days. The pyridine hydrochloride, formed as a byproduct of thisreaction, ordinarily precipitates and is separated from the reactionmixture by filtration. The filtrate is then mixed with water and anorganic water-immiscible solvent such as ether, chloroform, benzene,toluene, ylene and the like; washed with an aqueous solution of amineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,and the like, and then with Water. The ethereal solution is dried andevaporated to dryness under reduced pressure to produce, in the form ofan oily residue, the --c.orresponding 1- methyl-2-chloroethyl organicsulfonate, as for example 1 methyl-'2-.chloroethyl-D-toluenesulfonate,1-methyl-2echloroethyl-benzenesulfonate,1-methyl.-;2-chloroethyl-methanesulfonate, and the like.

This product is ordinarily purifiedb-y treatment with aqueouspy-ridineto convert the residual organic sulfonyl chloride to an acid. 7 Theresulting mixture is treated with an organic water-hm miscible solventand-aqueous hydrochloric acid and the layers are separated. The organicsolvent layeris washed first with an aqueous olution of a mineral acidand th n w h Water; th organic layer is then ,further purified, ifdesired, by washing with an aqueous alkaline solution such as aqueoussodium hydroxide, aqueous po- The etherlayer is separated and yellow oilwhich is ready for use in the reaction v with diphenyl acetonitrile.

The above procedure can a considerable excess of pyridine in thereaction between the organic sulfonyl chloride and propylenechlorohydrin. Under these conditions, there is an excess of pyridinepresent afterthepyridi'ne be varied by using hydrochloride is removed byfiltration. The addition of water at this point followed by a standingperiod results in complete hydrolysis of sul-" fonyl chloride. The stepof purifying the first oily residue is eliminated since the l-methyl-2-.chloroethyl organic sulfonate formed at this stage is of satisfactorypurity for employment in the subsequent reaction step.

The l-methyl-Z-chloroethyl organic sulfonate is treated with thereaction product of diphenylacetonitrile and sodamide. Thediphenylacetonitrile is mixed with an equivalent molar quantity ofsodamide and a liquid hydrocarbon, preferably a liquid having a boilingpoint of at least about 110 C., such as xylene, toluene, or liquidpetrolatum. The resulting mixture is heated and stirred until at leastabout 95% of the theoretical amount of ammonia has been liberated,-which ordinarily requires between about 3 and 5 hours. The reaction isordinarily carried out at a temperature of about 105-110 C. under refluxand in the presence of a nitrogen atmosphere.

This reaction mixtureis then cooled to between about 70 and 90 C. andthe l-methyl-2- chloroethyl organic sulfonate is added thereto rapidly,preferably keeping the temperature below about 90 C. The resultingmixture is then heated under reflux until the reaction is substantiallycomplete, which ordinarily requires about 14 to 18 hours. The reactionmixture is then mixed with water, and the organic layer is separated,washed'with water and dried. The organic layer is evaporated to drynessto produce a crude product which may be used, if desired, in thesubsequent reaction with dimethylamine. The crude product can bepurified by distillation in vacuo to produce substantially pure2,2-diphenyl 3 methyll-chloro-butyronitrile (compound 4) r As pointedout above, the nitrile product prepared in-this way consists only of thedesired 2,2-diphenyl 3 methyl-l-chloro-butyronitrile uncontaminated withany isomeric product. This drous dimethylamine.

are not harmful, but larger amounts result in 4 thus forming theunwanted 2,2-diphenyl-4- (organic-sulfonyl)-valeronitrile. The formationof this compound, in other than small amounts, would make the reactionimpractical.

The 2,2-diphenyl-3-methyl-4-chloro-butyronitrile is then reacted withsubstantially anhy- S'mall amounts of water a heterogeneous mixture ofreactants. It is therefore preferred to conduct the reaction undersubstantially anhydrous conditions. It is ordinarily desired t'o employan excess of dimethylamine in the-reaction. Since dimethylamine is a gasat room temperature, it is convenient to mix the reactants together at atemperature below about 7 C. The mixture of reactants is then heated ina pressure vessel to a temperature of approximately 100-150" C. Underthese conditions, the reaction is ordinarily complete in approximately48- hoursl If desired, the reaction can be carried out in the presenceof a solvent for therea'ctants, such as ethyl alcohol, and atatemperature of. about 100-150 C: It has beenfourid, however, that thepresence of an organic solvent, such as ethanol, tends to lower itheyield. It is ordinarily preferred therefore, to carry out the reactionutilizing dimethylamine and 2,2-diphenyl-3-methyl-4-chloro-butyronitrile asthe sole components; and to conductthe reaction at the higher temperature of 150 C. employing the longerreaction period (48 hours), since these conditions have been found toresult in the obtainment of a higher yield than that obtainable when thereaction is .carriedout in the presence of a solvent.

A mixture of Water and an. organic waterimmiscible solvent such. asether, chloroform, benzene, toluene, xylene, and the like, is then addedto the reaction mixture and the organic solvent layer is extracted withan aqueous solution of a mineral acid such as hydrobromic acid, sulfuricacid, and the like. The aqueous acid extracts are then neutralized withan inorganic base such as sodium hydroxide, potassium hydroxide,ammonium hydroxide and the like, and the aqueous alkaline solutionextracted with an organic water-immiscible solvent. The organic solventextractsare combined and evaporated to dryness in vacuo to produce crude2,2-diphenyl- 3-methyl-4dimethyl-amino-butyronitrile. Since thismaterial is obtained byreaction of dimethylamine with the single isomer,2,2-diphenyl-3- methyl-4chloro-butyronitrile, this product is likewiseuncontaminated with any isomeric nitrile material. The crude2,2-diphenyl-s3-methyl- 4-dimethylamino-butyronitrile can be used,without further treatment, for the production of isoamidone. It may:bepurified as follows: The crude material is dissolved in ether or otherorganic solvent, the ether solution issaturated wih dry hydrogenchloride gas, and the amine hydrochloride, which precipitates, isrecovered by filtration and recrystallized from absolute ethanol thusproducing the desired 2,2-diphenyl-3-. R

that the reaction would have taken place with M the elimination of thechlorine atom attached to the end carbon atom of the propane moiety toproduce substantially pure 2,2-diphenyl-3- methyl i-dimethylaminobutyronitrile hydrochloride. r

The following examples illustrate methods of carrying out the presentinvention, but his to be understood that these examples are given by wayof illustration and not of limitation.

Excinplel att red ture was cooled to c? C. To this suspension, 95.61 ofpropylene ,chlorohydrin were added siow1y, with stirring, keeping thetemperature at C. Stirring at 0 0., was continued for 3 hours. Thereaction mixture "was allowed to stand in an icebox for 24 hours, andwas then stirred at room temperature for about 40 hours.

Pyridine hydrochloride, which had precipitated, was removed byfiltration; and the illtrate was dilutedwith ether and water. The twolayers were separated, and the ethereal layer was washedsuccessivelyw'ith 2.5 N hydrochloric acid and water. The etherealsolution was dried and concentrated to dryness in vacuo.

To the oily residue, :79 gms. {of pyridine and '10 moi water were.added; and the solution was allowedto stand "l 'he'ur, to convertfres'idual ptbluenesu lfonyl chloride to the acid; Ether andhydrochloric 'a;"cid were added, and the layas were separated. Theethereal layer was washed successively with hydrochloric acid and water.The ethereal solution was dried and concentrated to dryness in vacuo.Therewas obtained in residue of 203.1 gms 181.3%) of 1-methyl-2-chloroethyl p-toluenesulfonate which was obtained in the formof a clear, light-yellow oil- I A portion or this oil was distilled; fitboiled at 106-118"C./0.1=0.25 mm, Analysis; Calc d for Ci'dHiiOtClh: C,48.29;}1, 5.27; CI, 14.28; found: C, 48.76.; H464; *Cl, 13.9.

Example 2 V In 158.2 gms. of pyridine were suspended 190.6 ems. ofp-toluenesul-fonyl "chloride, and the mixture was cooled to 0 3. Tosuspension, 94. 6 ems. or propylene chlorohydrin were added slowly, withstirring, keeping the temperature at 0 C. Stirring at 0 C. was continuedfor 1 hour. The reaction mixture was allowed to stand in an icebox forabout hours, and was then stirred at room temperature for about 24hours.

Pyridine hydrochloride, which had precipitated, was removed byfiltration. I To the filtrate were added 10 cc. of water, andthe's'olution was allowed to stand for 1 hour. Ether and hydrochloricacid were added and the layers were separated. The ethereal layer waswashed successively with hydrochloric acid, water, sodium hydroxide, andwater, The ethereal solution was dried and distilled in vacuo. There wasobtained 227 gms.- 9l-%) of 1-methyl-2-chloroethyl: D-toluenesulfonate,boiling point 119-120" C./0.c

Example 3 v In 158.2 gms. of pyridine were suspended 176.6 guns. ofbenzenesulfonyl chloride, and the mixture was cooled to 0 C. To thissuspension, 94.6 gm-s. of propylene chlorohydrin were added slowly, withstirring, keeping the temperature at 0 C. Stirring at 0 C., wascontinued for 1v 6. nate', boiling point 105- 106" CJOJ mm. .Zi n'alli-fsis: C'alcd for CsHnOsClS: C, 45.86; H, 4171': C1, 15.04; found: 'C,"4629; H, 4194; '01, 14.35

1 v Example 4 e In 79 .1 m. of pyridine were sus ended 57.3 ofmeth'anesulfonyl chloride, and the 'mixtin'e was'co'ol'ed'to 0 C. Tothis suspension, 47.3 gms. of prop lene ,chlorohydrinjwere added slowlywith stirring." keeping the temperature at 0 C. Stirrmg at 0" C;was'continue'd for 1 hour. The reaction mixture wasa'llo'wed to stand inan i ebox 'overnight, and wasft'hen stirred at room temperature forabout '24 hours.

The precipitate of pyridine hydrochloride was removed by filtration. Tothe filtrate was added 8 cc. of water, and the solution was stirred for1 hour. Benzene and hydrochloric acid were added-and the layers wereseparated. The benz ene layer waswas'hed successively with hydrochloric.acid, water and sodium hydroxide and water. The benzenesolution wasdried and distilledlin'vacuo. There was obtained 65 gm. (75.5%) of1-methyl-2-chloro-ethyl-methanesulfonate, boiling point 76.5 77 010.41Analysis: Calcd. for C'4H9O3GIS: C, 27.76.; H, 5.26,; C1, 2 0.'54;found; (2, 28.19; H, 5537; -.'Cl, "20181,

To 35.4 .gms. 10f 'sodamide under nitrogen, a solution of:1"75.-5:g'1ns. -'of dipher'iylacetonitrile 'in 1200 cc. or toluene wasadded rapidly. -,'Ih'e mixture was heated with stirring to 106 C., andmaintaine at this temperature tor about 3 /2 hours.

The reaction mixture was then 'cooledto 70 "0., and Y227 gm's. of. :lmethyl'd chloroethyleptoluenesulfonate were added rapidly, keeping thetemperature below 'C. The mixture was then heated atrefiux for about 18hours, cooled to 70 C'., and 500 cc. of water were .added. The 'organiclayer was separated, washed with water, and dried. It was then distilledin vacuo. There was obtained 1-40 g'ms. (51%) "of 2,2-diphenyl- 3 methyl4 e chlorobutyronitrile, boiling point 154-160 (L/0.2 m'm. Analysis:Calcd ifo'r C1'1I-I1sNC1: C, 75.68; H,5.98I;.N, 5.19;; Found: JC, 75.68;H, 5.90; N, 5.33.

Example 6 To 129 g ms. 'o so'darnide and run cc. of toluene, undernitrogen, "a solution of 38.6 ems. of diphenylacetonitrile 311 3000.oftoluene was added rapidly. The mixture was 'hea ted with stirring to-C., and maintained atthis temperature for about '3 hours. The reactionmixture was then co'oled'to' 65'" G-.', and 47. 2 g'ms.oily-methyla-chloroethyl benzenesulionate were added rapidly, keepingthe temperature below 85 C. The mixture was then heated at*re fl-ux forabout'lfi hours. cooled to 70 C2, and '500 "cc. of water were added. Theorganic layer was separated, washed with water and dried. "It was thendistilled in vacuo; There-was obtaine 37 gms. 69%) of 2,2 diphenyl 3 7methyl 4 chlorobutyrorii trile, boiling range 143-450 010.1? mm.Analysis: Caldd ffor CriHm NGl: 75168; 'H, 5.98; found: C."Z5311;- H,-6.05.- a

, Example ,7

To 13.6 gms. of sodam'i'de 'under nitrogen, a solution of 57.2 gms. ofdiphenylacetohitrilein 1390 ca e; toluene was addedgrapldly. j: mix:ture was heated with s'tl'rring' torus 0:, and

mai taine t,..-th. s temper tur about 5 hours; :12.-

:1-1'151 i 1 Thereaction mixture was then cooled to 90 0., and 60 gms.of 1-methyl-2-chlorethyl methanesulfonate were added rapidly, keepingthe temperature below 90" C. The mixture wa then heated at reflux forabout'1'4 hours, cooled to room temperature and 500cc. of. water wereadded." The organicl'ayer'was'separated, washed with" water, and dried:'ItTwas then'distilled in vacuo. .There wa'siobtainedfiofgm's. (52.7%)of 2,2 diphen'yl -'-'f3' niethyl '2' 4'-'chlorobutyroni trile, boilingrange 116-128 C'./0;04 mm. Analysis: Calcd for CnHwNCl: C, 75.68; H,5.98; N, 5.19; Cl, 13.15; found: 'C, 76.06; H,16;34; N; 4.89; 01,12.74.i

. r Example, 8 V

' In 20 DC. of absoluteethanol weredissolved 5 gms; of 2,2 a diphenyl3'-f-'methyl 4 chlorobutyronitrile, and the solution was cooled in a DryIce-acetone bath. The cold' solution was added to 20 'cc. of anhydrousdimethylamine, cooled ina Dry Ice-acetone bath. The mixture was thensealed in a'bomb tube and heated overnight at 100 0. v

The contents of the tube were concentrated to dryness in vacuo, and tothe residue was added ether and water. The layers were separated, and

the ether layer was extracted with hydrochloric acid. The acid extractswere made alkaline with sodium hydroxide, and were then extracted withether. The ethereal extracts were dried and concentrated to dryness invacuo. The residue crystallized on cooling and scratching.

The residue was dissolved in ether and saturatedwith dry HClJgasr2,2-dipheny1-3-methyl- 4edimethylamino-#butytronitrile hydrochloroideprecipitated,wasremoved by filtration, and was recrystallized fromabsolute ethanol, M. P. 218-220 0. The mixed melting point with anauthentic'sample of the. nitrile hydrochloride was 218-220 C. Comparisonof the product with an authentic sample of the nitrile hydrochloride bymeans of infra-red: spectra showed the two compounds to be identical.Analysis: Calcd for C19H23N2C'1::C,.'72.48; H, 7.36; N, 8.90; found: C,72.34; H, 7.24; N, 9.09. i

Example 9 To 20 cc. of anhydrous dimethylamine cooled in a DryIce-acetone bath were added 20 guns. of 2,2 -Vdip n 1 .--;3 '-,.m hy 4 hor utyro trile, he mixture was sealed in a bomb tube and heated ,at150C. 01148 hours. V

Ether and water were added to the reaction mixture, and the two layersformed were separated. The ethereal layer was extracted withhydrochloric. acid. The acid extracts were neutralized with sodiumhydroxide and extracted with ether. The .ether extracts wereconcentrated to dryness in vacuo. There was obtained a residue of 9.8gms. (47.5%) of 2,2-diphenyl-3- methyl 4 dimethylamino butyronitrile.This can be purified, if desired, as outlined in Example 8. I V Variouschanges ,and modifications may be made in our invention withoutdeparting from the spirit and scope thereof; Insofar as these changesand modifications are within the purview of the annexed claims, they areto be considered as part of our invention. 'Weclaimr r '1. The processwhich comprises reacting propylene fchlorohydrinl with .an organicsulfonyl halide, reacting the resulting sulfonate with thecondensationk'product of diphenyl-acetonitrile and sodamide,] andreacting the compound thus formed with dimethylaminef a 2. The processwhich comprises reacting propylene chlorohydrin with p toluenesulfonylchloride in the presence of pyridine, reactingfthe resulting s-ulfonate,in the presence of a liquid hydrocarbon, with the condensation productof diphenylacetonitrile and sodamide and reactin the compound thusformed with dimethylamine, said reaction; being carried out by heatingthe reactants under pressure at a temperature of approximately -150" C.

3. The process which comprises reacting propylene chlorohydrm withbenzenesulfonyl chloride in the presence of pyridine, reacting theresulting sulfonate, in the presence of a liquidhydrocarbon, with thecondensation product of diphenylacetonitrile and sodamide, and reactingthe compound thus formed with dimethylamine, said reaction being carriedout by heating the reactants under pressure at a temperature ofapproximately 100 C.

4. The process which comprises reacting propylene chlorohydrin withmethane sulfonyl chloride in the presence of pyridine, reacting theresulting sulfonate, in the presence of a liquid hydrocarbon, with thecondensation product of diphenylacetonitrile and sodamide, and reactingthe compound thus formed with dimethylamine, said reaction being carriedout by heating the reactants under pressure at a temperature ofapproximately 100-150 C. v

5, The process of preparing 2,2-diphenyl-3- methyl 4 dimethylaminobutyronitrile which comprises reacting substantially anhydrousdimethylamino with- 2,2 diphenyl 3 methyl- 4-chloro-butyronitrile, saidreaction being carried out by heating the reactants together underpressure at a temperature of approximately 100-150 o.

6. The process of preparing 2,2-diphenyl-3- methyl 4 dimethylaminobutyronitrile which comprises reacting substantially anhydrousdimcthylamine with 2,2- diphenyl 3 methyl- 4-chloro-butyronitrile, saidreaction being carried out by heating an ethanol solution of thereactants under pressure at a temperature of approximately 100-150C. I a

. EARL-M. CHAMBERLIN.

MAX TISI -ILER.

REFERENCES CITED The following references are of record in the fileofthis patent:

UNITED STATES PATENTS Number I Name Date 2,042,222 Groll et al. 'May 26,1936 2,139,669 Bucl Dec. 13, 1938 2,230,774 Bockmuhl et a1 Feb. 4, 19412,419,488 Dutcher Apr. 22, 1947 2,443,292 'Bauer et al June 15, 19482,459,420 Erickson Jan. 18, 1949

1. THE PROCESS WHICH COMPRISES REACTING PROPYLENE CHLOROHYDRIN WITH ANORGANIC SULFONYL HALIDE, REACTING THE RESULTING SULFONATE WITH THECONDENSATION PRODUCT OF DIPHENYL-ACETONITRILE AND SODAMIDE, AND REACTINGTHE COMPOUND THUS FORMED WITH DIMETHYLAMINE.